A major locus confers triclabendazole resistance in Fasciola hepatica and shows dominant inheritance.
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
01 2023
01 2023
Historique:
received:
02
10
2022
accepted:
22
12
2022
revised:
07
02
2023
pubmed:
27
1
2023
medline:
10
2
2023
entrez:
26
1
2023
Statut:
epublish
Résumé
Fasciola hepatica infection is responsible for substantial economic losses in livestock worldwide and poses a threat to human health in endemic areas. The mainstay of control in livestock and the only drug licenced for use in humans is triclabendazole (TCBZ). TCBZ resistance has been reported on every continent and threatens effective control of fasciolosis in many parts of the world. To date, understanding the genetic mechanisms underlying TCBZ resistance has been limited to studies of candidate genes, based on assumptions of their role in drug action. Taking an alternative approach, we combined a genetic cross with whole-genome sequencing to localise a ~3.2Mbp locus within the 1.2Gbp F. hepatica genome that confers TCBZ resistance. We validated this locus independently using bulk segregant analysis of F. hepatica populations and showed that it is the target of drug selection in the field. We genotyped individual parasites and tracked segregation and reassortment of SNPs to show that TCBZ resistance exhibits Mendelian inheritance and is conferred by a dominant allele. We defined gene content within this locus to pinpoint genes involved in membrane transport, (e.g. ATP-binding cassette family B, ABCB1), transmembrane signalling and signal transduction (e.g. GTP-Ras-adenylyl cyclase and EGF-like protein), DNA/RNA binding and transcriptional regulation (e.g. SANT/Myb-like DNA-binding domain protein) and drug storage and sequestration (e.g. fatty acid binding protein, FABP) as prime candidates for conferring TCBZ resistance. This study constitutes the first experimental cross and genome-wide approach for any heritable trait in F. hepatica and is key to understanding the evolution of drug resistance in Fasciola spp. to inform deployment of efficacious anthelmintic treatments in the field.
Identifiants
pubmed: 36701396
doi: 10.1371/journal.ppat.1011081
pii: PPATHOGENS-D-22-01707
pmc: PMC9904461
doi:
Substances chimiques
Triclabendazole
4784C8E03O
Benzimidazoles
0
Anthelmintics
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1011081Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/1002480/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/P001912/1
Pays : United Kingdom
Informations de copyright
Copyright: © 2023 Beesley et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Déclaration de conflit d'intérêts
The authors declare that they have no competing interests.
Références
Emerg Infect Dis. 2012 Jun;18(6):1028-9
pubmed: 22607719
Nucleic Acids Res. 2017 Jan 4;45(D1):D190-D199
pubmed: 27899635
Mol Biochem Parasitol. 1993 Jun;59(2):327-9
pubmed: 8341329
Mol Biochem Parasitol. 2012 Nov;186(1):69-72
pubmed: 22982092
Nat Biotechnol. 2015 Mar;33(3):290-5
pubmed: 25690850
Mol Biochem Parasitol. 2012 Jan;181(1):37-9
pubmed: 22001370
Pharmacol Ther. 1993 Nov;60(2):331-6
pubmed: 8022863
Nat Protoc. 2016 Sep;11(9):1650-67
pubmed: 27560171
Vet Parasitol. 2006 Dec 20;142(3-4):281-92
pubmed: 16973288
Infect Genet Evol. 2015 Jun;32:298-304
pubmed: 25796359
J Proteome Res. 2010 Oct 1;9(10):4940-51
pubmed: 20726552
Vet Parasitol. 2013 Mar 31;193(1-3):307-11
pubmed: 23265810
Lancet Infect Dis. 2012 Mar;12(3):210-21
pubmed: 22108757
Int J Parasitol. 2016 Jun;46(7):417-24
pubmed: 27073078
Vet Parasitol. 2013 Jan 31;191(3-4):379-85
pubmed: 23021260
Int J Parasitol. 2013 Dec;43(14):1133-9
pubmed: 24162076
Mol Biochem Parasitol. 2008 May;159(1):73-8
pubmed: 18372053
Vet Parasitol. 2013 Jul 1;195(1-2):72-86
pubmed: 23597772
Mol Biochem Parasitol. 1986 Nov;21(2):139-49
pubmed: 3097538
Parasitol Int. 2013 Dec;62(6):639-46
pubmed: 23474412
Genome Biol. 2015 Apr 03;16:71
pubmed: 25887684
J Parasitol. 2006 Dec;92(6):1355-60
pubmed: 17304820
PLoS Pathog. 2022 Jun 13;18(6):e1010545
pubmed: 35696434
PLoS Negl Trop Dis. 2012 Jan;6(1):e1455
pubmed: 22253936
BMC Bioinformatics. 2011 Dec 22;12:491
pubmed: 22192575
Am J Hum Genet. 2001 Apr;68(4):978-89
pubmed: 11254454
Mol Biochem Parasitol. 2014 Nov;198(1):45-7
pubmed: 25481750
J Proteome Res. 2016 Sep 2;15(9):3308-21
pubmed: 27495901
Int J Parasitol Drugs Drug Resist. 2020 Apr;12:39-59
pubmed: 32179499
J Helminthol. 2005 Sep;79(3):227-34
pubmed: 16153316
Int J Parasitol. 2011 Nov;41(13-14):1347-59
pubmed: 22019596
Nucleic Acids Res. 2016 Jan 4;44(D1):D774-80
pubmed: 26578572
Exp Parasitol. 1993 Dec;77(4):445-9
pubmed: 8253157
Nucleic Acids Res. 2015 Jan;43(Database issue):D250-6
pubmed: 25428351
Prev Vet Med. 2015 Sep 1;121(1-2):41-8
pubmed: 26093971
BMC Genomics. 2019 Mar 15;20(1):218
pubmed: 30876405
Acta Trop. 2019 Nov;199:105158
pubmed: 31491399
Nat Rev Genet. 2007 Jul;8(7):497-506
pubmed: 17572690
Bioinformatics. 2015 Oct 1;31(19):3210-2
pubmed: 26059717
Vet Parasitol. 2011 Aug 25;180(3-4):237-42
pubmed: 21459514
Vet Parasitol. 2011 Aug 4;180(1-2):133-43
pubmed: 21703766
Vet Rec. 2019 Apr 20;184(16):502
pubmed: 30824600
Geospat Health. 2015 Mar 19;9(2):301-8
pubmed: 25826311
Vet Parasitol. 2009 Aug 26;163(4):293-7
pubmed: 19556065
Nucleic Acids Res. 2017 Jan 4;45(D1):D158-D169
pubmed: 27899622
Genome Biol Evol. 2018 Sep 1;10(9):2458-2473
pubmed: 30165630
Science. 1986 May 9;232(4751):751-5
pubmed: 2421411
Front Cell Infect Microbiol. 2022 Feb 10;12:811123
pubmed: 35223544
Nat Genet. 2011 May;43(5):491-8
pubmed: 21478889
Rev Med Chil. 2014 Oct;142(10):1330-3
pubmed: 25601119
PLoS Genet. 2017 Jan 6;13(1):e1006537
pubmed: 28060841
Mol Ecol Resour. 2010 May;10(3):564-7
pubmed: 21565059
Parasitol Res. 2004 Feb;92(3):205-10
pubmed: 14652740
Science. 2013 Dec 13;342(6164):1385-9
pubmed: 24263136
Parasitology. 2013 Oct;140(12):1523-33
pubmed: 23721579
J Biol Chem. 1960 Feb;235:466-70
pubmed: 14420764
Bioinformatics. 2011 Nov 1;27(21):2987-93
pubmed: 21903627
Nucleic Acids Res. 2005 Nov 27;33(21):6688-93
pubmed: 16314301
J Helminthol. 2009 Jun;83(2):139-50
pubmed: 19366485
J Helminthol. 2019 Mar 18;94:e46
pubmed: 30880654
PLoS Negl Trop Dis. 2016 Jan 25;10(1):e0004361
pubmed: 26808543
PLoS One. 2013 May 08;8(5):e64337
pubmed: 23667708
Trends Parasitol. 2016 Jun;32(6):458-469
pubmed: 27049013
Mol Biochem Parasitol. 2018 Sep;224:57-60
pubmed: 30055185
Bull World Health Organ. 1995;73(3):397-9, 403-5
pubmed: 7614672
Mol Pharmacol. 1978 Sep;14(5):804-19
pubmed: 714024
Nat Methods. 2012 Mar 04;9(4):357-9
pubmed: 22388286
Trends Parasitol. 2018 Nov;34(11):982-996
pubmed: 30150002
Nat Commun. 2012 May 22;3:853
pubmed: 22617293
Annu Rev Pharmacol Toxicol. 2003;43:285-307
pubmed: 12359865
Vet Parasitol. 2012 Feb 28;184(1):37-47
pubmed: 21872399
Parasit Vectors. 2018 Jun 26;11(1):363
pubmed: 29941045
Comp Biochem Physiol C Toxicol Pharmacol. 2006 Mar-Apr;142(3-4):262-274
pubmed: 16423563
Vet Rec. 2005 Nov 5;157(19):578-82
pubmed: 16272544
Vet Rec. 1983 Oct 1;113(14):315-7
pubmed: 6649348
Eukaryot Cell. 2009 Aug;8(8):1085-93
pubmed: 19465561
Int J Parasitol. 2017 Jan;47(1):11-20
pubmed: 27940066
PLoS One. 2011 Jan 10;6(1):e16126
pubmed: 21249228
PLoS Negl Trop Dis. 2021 Oct 5;15(10):e0009750
pubmed: 34610021
Front Cell Infect Microbiol. 2017 Nov 06;7:452
pubmed: 29209592
Nat Genet. 2014 Dec;46(12):1350-5
pubmed: 25326702
Parasitology. 2002 Mar;124(Pt 3):325-38
pubmed: 11922434
Parasitology. 2005 Oct;131(Pt 4):501-10
pubmed: 16174415
Biochem Pharmacol. 1984 Sep 1;33(17):2789-97
pubmed: 6466386
Vet Parasitol. 2009 Dec 23;166(3-4):235-40
pubmed: 19836140
Exp Parasitol. 2013 Nov;135(3):642-53
pubmed: 24090567
Biochem Pharmacol. 1979 Jun 15;28(12):1943-6
pubmed: 88227
PLoS One. 2014 Nov 19;9(11):e112963
pubmed: 25409509
Int J Parasitol. 2012 May 15;42(6):529-34
pubmed: 22475816
Res Vet Sci. 2005 Apr;78(2):177-81
pubmed: 15563926
Sci Transl Med. 2021 Dec 22;13(625):eabj9114
pubmed: 34936381
Int J Parasitol. 2008 Feb;38(2):149-55
pubmed: 18048044
Biotechnol Adv. 2018 Jul - Aug;36(4):894-904
pubmed: 29454982
Insect Mol Biol. 2005 Oct;14(5):509-21
pubmed: 16164607
Bioinformatics. 2016 Mar 1;32(5):767-9
pubmed: 26559507
Mol Pharmacol. 1976 Jan;12(1):49-58
pubmed: 176567
Mol Biol Evol. 2020 Jan 1;37(1):84-99
pubmed: 31501870
Parasitology. 2013 Sep;140(10):1287-303
pubmed: 23756576
Int J Parasitol. 2009 Jul 1;39(8):915-24
pubmed: 19254720
Parasitol Res. 2010 May;106(6):1351-63
pubmed: 20336319
Vet Rec. 2012 Aug 11;171(6):153, 1-5
pubmed: 22791519
Mol Biochem Parasitol. 2017 Jul;215:2-10
pubmed: 27899279
Mol Pharmacol. 1978 Sep;14(5):820-33
pubmed: 30890
Prev Vet Med. 2007 Jan 16;78(1):57-66
pubmed: 17095109
Nat Commun. 2014 Jul 09;5:4378
pubmed: 25007141
PLoS Pathog. 2019 Oct 25;15(10):e1007881
pubmed: 31652296
Exp Parasitol. 2015 Dec;159:274-9
pubmed: 26542261
Am J Trop Med Hyg. 1984 Jan;33(1):80-8
pubmed: 6696189
Am J Hum Genet. 2003 Nov;73(5):1162-9
pubmed: 14574645
Genome Res. 2016 Mar;26(3):342-50
pubmed: 26848124
PLoS Negl Trop Dis. 2016 Sep 13;10(9):e0004994
pubmed: 27622752